The information provided herein is intended solely to assist the understanding of the reader. None of the information provided nor references cited is admitted to be prior art to the present invention.
The identification of the molecular events that underlie the development of human diseases presents a major challenge in the design of improved strategies in the prevention, management, and cure of certain diseases (Lahiry P et al. Kinase mutations in human disease: interpreting genotype-phenotype relationships. Nat Rev Genet. 2010; 11(1):60-74).
The role of aberrantly regulated protein tyrosine kinases (PTKs) in human diseases is the subject of intense investigation (Lahiry id.). Protein kinases are regulators of cellular signaling, and their functional dysregulation is common in carcinogenesis, autoimmune reactions, and many other disease states or conditions (Lahiry id.; Vargas L et al. Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases. Scand J Immunol. 2013; 78(2):130-9; Nobel M E et al. Protein kinase inhibitors: insights into drug design from structure. Science. 2004; 303:1800-1805). The human genome encodes over 500 protein kinases that share a catalytic domain conserved in sequence and structure but which are notably different in how their catalysis is regulated (Manning G et al. The protein kinase complement of the human genome. Science. 2002; 298:1912-1934; Nobel id.). Protein kinases regulate key signal transduction cascades that control or are involved in the control of physiological functions, including cellular growth and proliferation, cell differentiation, cellular development, cell division, stress response, transcription regulation, aberrant mitogenesis, angiogenesis, abnormal endothelial cell-cell or cell-matrix interactions during vascular development, inflammation, Jun-N-terminal kinase (JNK) signal transduction, and several other cellular processes (Manning id). Protein kinase inhibitors have been established as promising drugs that inhibit overactive protein kinases in cancer cells (Gross S et al. Targeting cancer with kinase inhibitors. J Clin Invest. 2015; 125(5):1780-1789; Vargas id).
A partial, non-limiting list of kinases includes: ABL, ACK, ARG, BLK, BMX, BRK, BTK, CSK, DDR1, DDR2, EGFR, EPHA1, FGR, FMS, FRK, FYN(isoform a), FYN(isoform b), HCK, KIT, LCK, LYNa, PDGFRα, PDGFRβ, SRC, SRM, YES, PIK3CA/PIK3R1 (Manning id). Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative conditions as well as diseases resulting from inappropriate activation of the immune and nervous systems.
The novel compounds of this invention inhibit the activity of one or more protein kinases and are expected to be useful in treating kinase-related diseases or conditions.